Alveolar echinococcosis in particular can be regarded as the most dangerous parasitosis in humans in Central Europe (W., Frank in: Raumliche Persistenz und Diffusion von Krankheiten [W. Fricke, E. Hinz, Hrsg.], Heidelb. Geoqr. Arb. 83:86-113 (1987)).
This estimate is also supported by the World Health Organisation (WHO).
Infection with eggs of Echinococcus usually has catastrophic consequences for man when he is an accidental intermediate host.
The growth of the bladder worm in the case of E. multilocularis is slower in man than in the natural intermediate hosts, protoscolesces are frequently not even formed and central necrosis processes are typical. The disease often affects human health to the extent that it may result in death. According to 1. Drolshammer et al., Schweiz. med Wschr. 103:1337-1386 (1973), mortality after an average period of 3.7 years is 52% after diagnosis and according to H.J. Schicker, Inaugural Diss. Med. Fak. University Tubingen (1976), about 20% survive for 5 years after diagnosis.
The pattern of the disease in man is furthermore extremely insidious. This is because diagnosis is made too late in the majority of cases, so that after the first symptoms of echinococcosis have appeared, with an attack on the liver, the chances of survival are very slight and only an unfavourable prognosis can be given.
In the time which has elapsed since echinococcosis was first described by Virchow in 1856 up to 1974, operative intervention was the only method of increasing the survival time or, in rare cases, effecting a cure. In 1974-75 the benzimidazoles were . then discovered for chemotherapy, including mebendazole (methyl [5-benzoyl-benzimidazol-2-carbamate]) (Campell, W.C. et al.. J. Parasitol. 61:844-852 (1975); Heath, D.D. et al.. Parasitology 70:273-285 (1975)).
Hitherto, mebendazole has generally been the only agent used in cases of alveolar echinococcosis. However, prognosis has remained unsatisfactory since this substance usually only has a parasitostatic effect in spite of being taken every day and its use is not entirely without problems. In addition, the mebendazole treatment does not totally cure the infection and once the treatment is discontinued the proliferative growth of the parasite stage (metacestode) may start up again. Then, in the last analysis, the only chance is an operation, again with an uncertain prognosis.
Benzimidazoles inhibit the synthesis of the microtubuli by binding to the dimeric component, tubulin (H. Van den Bossche et al.. In: Advances in pharmacology and chemotherapy. Vol. 19 [S. Garattini, A. Goldin, F. Hawkins, Kopin, Hrsg.], Academic Press New York, 67-128 (1982)). However, the binding affinity is not the same for each tubulin.
It is known from P.A. Friedmann & E.G. Platzer, Biochem. Biophys. Acta 630:271-278 (1980), that mebendazole binds 384 times more strongly to embryonic Ascaris suum-tubulin than to cattle brain tubulin, for example. Microtubuli are part of the cellular cytoskeleton and, in addition to their supporting function, also participate in the formation of the mitosis spindle and in intracellular transportation. Consequences of the benzimidazole activity may include cell division disorders, inhibition of the uptake of glucose (H. Van den Bossche, in Comparative biochemistry of parasites [H. Van den Bossche, Hrsg.], Academic Press, New York, 139-157 (1972)) with greater degradation of endogenous glycogen and inhibition of ATP synthesis (M.S. Rahman & C. Bryant, Int. J. Parasitol. 7:403-409 (1977)). The merely parasitostatic effect of mebendazole on Echinococcus multilocularis is based inter alia on the purely physical effect of the impaired diffusion of the active substance through the spongy cyst tissue, with a gelatinous lumen content, compared with Echinococcus granulosus (A. Dieckmann, Dissertation, Faculty II (Biol), University of Hohenheim (1987)).
The mebendazole therapy for human echinococcosis was started about 13 years ago. Today, it is still beset with many problems. For ethical reasons and on account of the high mortality rate it has not hitherto been possible to carry out any human experiments e.g. to discover the minimum effective concentration of mebendazole. Furthermore, there is no clear correlation between the dose and blood level. Further problems arise with the absence of reliable criteria for rapidly checking the success or failure of a therapy and insufficient knowledge of the nature and cause of side effects.
Nowadays, in general, a long term therapy of 40-50 mg/kg per day is the aim in inoperable or nonradically operated and recurring Echinococcus multicularis (R. Ammann et al.. in: Probleme der Echinokokkose unter Berucksichtigung parasitologischer und klinischer Aspekte [R. Bahr, Hrsg.], Huber Verlag Bern. Aktuel. Probl. Chir. OrthoD. 23:92-95 (1982); H. Biedermann ibidem. 98-99; U. Junge & P. Friedl, ibidem. 100-103; P. Kern & M. Dietrich, ibidem. 104-105).
Hitherto, it has been possible to achieve an improvement in the quality of life (H. Biedermann (1982), loc. cit.: U. Junge & P. Friedl, (1982), loc. cit.: P. Kern & M. Dietrich (1982), loc. cit.), a partial reduction in the Echinococcus AK titre (U. Junge & P. Friedl, (1982) loc. cit.), but no or only a slight regression in the intrahepatic tumour mass (R. Ammann et al. (1982), loc. cit.: P. Kern & M. Dietrich (1982), loc. cit.). R. Ammann et al.. (1982), loc. cit.. was able to detect active larval material in Echinococcus material removed by operating on 3 patients. This again appears to confirm the exclusively parasitostatic effect of mebendazole in Echinococcus infections.
IFN.gamma. has hitherto been used mainly in virus, tumour or autoimmune diseases o to combat the pain which accompanies these diseases (S. Levin, Isr. J. Med. Sci. 19:955-958 (1983); K. Osther et al.. Proceedings of the Second International TNO Meeting on the Biology of the Interferon System, 18-22 Apr. 1983, in: The Biology of the Interferon System (1983) [Edward De Maeyer & Huub Schellekens, Eds.]Elsevier Science Publishers B.V., 527-533 (1983)).
In addition to these applications, it has been proposed that IFN.gamma. be used in intracellular bacterial infections as well (A.F. Kiderlen et al.. Eur. J. Immunol. 14:964-967 (1984); J. Mauel, Y. Buchmuller Rouiller, Eur. J. Immunol. 17:203-208 (1987)).
Furthermore, IFN.gamma. has only been used to treat infections caused by parasitic protozoa (I.A. Clark et al.. J. Immunol. 139:3493-3496 (1987); A.F. Kiderlen M.L. Lohmann-Matthes, Interdisciplinary conference on primary health care in the tropics, tropical diseases and zoonoses, 13.-15. Apr. 1987, Genf; S.G. Reed, J. Immunol. 140(12):4342-4347 (1988); Y. Suzuki et al.. Science 240:516-518 (1988)). However, the effectiveness of this type of therapy was uncertain and in some cases even discouraging.